bims-midneu 2021-05-23 papers

bims-midneu

Biomed News

on Mitochondrial dysfunction in neurodegeneration

Issue of 2021‒05‒23
twenty papers selected by
Radha Desai
Merck Sharp & Dohme Corp.

PINK1 Activation Attenuates Impaired Neuronal-Like Differentiation and Synaptogenesis and Mitochondrial Dysfunction in Alzheimer's Disease Trans-Mitochondrial Cybrid Cells.
Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes.
Rapamycin activates mitophagy and alleviates cognitive and synaptic plasticity deficits in a mouse model of Alzheimer's disease.
The Protective Mechanism of SIRT1 in the Regulation of Mitochondrial Biogenesis and Mitochondrial Autophagy in Alzheimer's Disease.
High-throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblasts.
Mitochondrial survivin reduces oxidative phosphorylation in cancer cells by inhibiting mitophagy.
Role of conserved regions of Tim22 in the structural organization of the carrier translocase.
Glycolytic Metabolism, Brain Resilience, and Alzheimer's Disease.
A new brain mitochondrial sodium-sensitive potassium channel: effect of sodium ions on respiratory chain activity.
In vivo assay and modelling of protein and mitochondrial turnover during aging.
Mitochondrial damage and senescence phenotype of cells derived from a novel frataxin G127V point mutation mouse model of Friedreich's ataxia.
Mitochondrial-nuclear heme trafficking is regulated by GTPases in control of mitochondrial dynamics and ER contact sites.
Cardiolipin is required for membrane docking of mitochondrial ribosomes and protein synthesis.
The Protective Effects of Dexmedetomidine against Hypoxia/Reoxygenation-Induced Inflammatory Injury and Permeability in Brain Endothelial Cells Mediated by Sigma-1 Receptor.
Mitochondrial dysfunction in Alzheimer's disease: Opportunities for drug development.
Intranasal delivery of mitochondria for treatment of Parkinson's Disease model rats lesioned with 6-hydroxydopamine.
Targeting the mitochondrial chaperone TRAP1: strategies and therapeutic perspectives.
The effect of Crocin on TFAM and PGC-1α expression and Catalase and Superoxide dismutase activities following cholestasis-induced neuroinflammation in the striatum of male Wistar rats.
NPC1 regulates the distribution of phosphatidylinositol 4-kinases at Golgi and lysosomal membranes.
Perinuclear mitochondrial clustering, increased ROS levels, and HIF1 are required for the activation of HSF1 by heat stress.

J Alzheimers Dis. 2021 May 14.

PINK1 Activation Attenuates Impaired Neuronal-Like Differentiation and Synaptogenesis and Mitochondrial Dysfunction in Alzheimer's Disease Trans-Mitochondrial Cybrid Cells.

Fang Du, Qing Yu, Shirley ShiDu Yan.

  BACKGROUND: Mitochondrial dysfunction, bioenergetic deficit, and extensive oxidative stress underlie neuronal perturbation during the early stage of Alzheimer's disease (AD). Previously, we demonstrated that decreased PTEN-induced putative kinase 1 (PINK1) expression is associated with AD pathology in AD-affected human brains and AD mice.OBJECTIVE: In the present study, we highlight the essential role of PINK1 in AD-relevant mitochondrial perturbation and neuronal malfunction.
METHODS: Using trans-mitochondrial "cybrid" (cytoplasmic hybrid) neuronal cells, whose mitochondria are transferred from platelets of patients with sporadic AD, we observed the effect of PINK1 in neuronal-like differentiation and synaptogenesis and mitochondrial functions.
RESULTS: In AD cybrid cells, the downregulation of PINK1 is correlated to the alterations in mitochondrial morphology and function and deficit in neuronal-like differentiation. Restoring/increasing PINK1 by lentivirus transduction of PINK1 robustly attenuate mitochondrial defects and rescue neurite-like outgrowth. Importantly, defective PINK1 kinase activity fails to reverse these detrimental effects. Mechanistically, AD cybrid cells reveal a significant decrease in PINK1-dependent phosphorylated mitofusin (Mfn) 2, a key mitochondrial membrane protein that participates in mitochondrial fusion, and an insufficient autophagic activity for clearance of dysfunctional mitochondria. Overexpression of PINK1, but not mutant PINK1 elevates phosphorylation of Mfn2 and autophagy signaling LC3-II. Accordingly, PINK1-overexpressed AD cybrids exhibit increases in mitochondrial length and density and suppressed reactive oxygen species. These results imply that activation of PINK1 protects against AD-affected mitochondrial dysfunction and impairment in neuronal maturation and differentiation.
CONCLUSION: PINK1-mediated mitophagy is important for maintaining mitochondrial health by clearance of dysfunctional mitochondria and therefore, improves energy homeostasis in AD.

Keywords:  Alzheimer’s disease; PINK1; cybrid cells; mitochondrial dysfunction; mitophagy

DOI:  https://doi.org/10.3233/JAD-210095
Cell Rep. 2021 May 18. pii: S2211-1247(21)00473-3. [Epub ahead of print]35(7): 109134

Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes.

Raja Bhattacharyya, Sophia E Black, Madhura S Lotlikar, Rebecca H Fenn, Mehdi Jorfi, Dora M Kovacs, Rudolph E Tanzi.

  Axonal generation of Alzheimer's disease (AD)-associated amyloid-β (Aβ) plays a key role in AD neuropathology, but the cellular mechanisms involved in its release have remained elusive. We previously reported that palmitoylated APP (palAPP) partitions to lipid rafts where it serves as a preferred substrate for β-secretase. Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are cholesterol-rich lipid rafts that are upregulated in AD. Here, we show that downregulating MAM assembly by either RNA silencing or pharmacological modulation of the MAM-resident sigma1 receptor (S1R) leads to attenuated β-secretase cleavage of palAPP. Upregulation of MAMs promotes trafficking of palAPP to the cell surface, β-secretase cleavage, and Aβ generation. We develop a microfluidic device and use it to show that MAM levels alter Aβ generation specifically in neuronal processes and axons, but not in cell bodies. These data suggest therapeutic strategies for reducing axonal release of Aβ and attenuating β-amyloid pathology in AD.

Keywords:  AD; APP; Alzheimer's disease; MAMs; axonal Abeta; lipid rafts; mitochondria-associated ER membranes; palmitoylation

DOI:  https://doi.org/10.1016/j.celrep.2021.109134
J Gerontol A Biol Sci Med Sci. 2021 May 18. pii: glab142. [Epub ahead of print]

Rapamycin activates mitophagy and alleviates cognitive and synaptic plasticity deficits in a mouse model of Alzheimer's disease.

Hui Wang, Jingxuan Fu, Xinxin Xu, Zhuo Yang, Tao Zhang.

  Alzheimer's disease (AD) is a chronic neurodegenerative disease, which is characterized by cognitive and synaptic plasticity damage. Rapamycin is an activator of autophagy/mitophagy, which plays an important role in identifying and degrading damaged mitochondria. The aim of this study was to investigate the effect of rapamycin on cognitive and synaptic plasticity defects induced by AD, and further explore if the underlying mechanism was associated with mitophagy. The results show that rapamycin increases parkin-mediated mitophagy and promotes fusion of mitophagosome and lysosome in the APP/PS1 mouse hippocampus. Rapamycin enhances learning and memory viability, synaptic plasticity and the expression of synapse related proteins, and impedes Cytochrome C-mediated apoptosis, decreases oxidative status and recovers mitochondrial function in APP/PS1 mice. The data suggest that rapamycin effectively alleviates AD-like behaviors and synaptic plasticity deficits in APP/PS1 mice, which is associated with enhanced mitophagy. Our findings possibly uncover an important function of mitophagy in eliminating damaged mitochondria to attenuate Alzheimer's disease-associated pathology.

Keywords:  Apoptosis; Dementia; Mitophagy; Oxidative stress; Rapamycin

DOI:  https://doi.org/10.1093/gerona/glab142
J Alzheimers Dis. 2021 May 11.

The Protective Mechanism of SIRT1 in the Regulation of Mitochondrial Biogenesis and Mitochondrial Autophagy in Alzheimer's Disease.

Fan Ye, Anshi Wu.

  Silent information-regulated transcription factor 1 (SIRT1) is the most prominent and widely studied member of the sirtuins (a family of mammalian class III histone deacetylases). It is a nuclear protein, and the deacetylation of the peroxisome proliferator-activated receptor coactivator-1 has been extensively implicated in metabolic control and mitochondrial biogenesis and is the basis for studies into its involvement in caloric restriction and its effects on lifespan. The present study discusses the potentially protective mechanism of SIRT1 in the regulation of the mitochondrial biogenesis and autophagy involved in the modulation of Alzheimer's disease, which may be correlated with the role of SIRT1 in affecting neuronal morphology, learning, and memory during development; regulating metabolism; counteracting stress responses; and maintaining genomic stability. Drugs that activate SIRT1 may offer a promising approach to treating Alzheimer's disease.

Keywords:  Alzheimer’s disease; SIRT1; mitochondrial autophagy; protective mechanism

DOI:  https://doi.org/10.3233/JAD-210132
EMBO Mol Med. 2021 May 20. e13579

High-throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblasts.

Emma Cretin, Priscilla Lopes, Elodie Vimont, Takashi Tatsuta, Thomas Langer, Anastasia Gazi, Martin Sachse, Patrick Yu-Wai-Man, Pascal Reynier, Timothy Wai.

  Mutations in OPA1 cause autosomal dominant optic atrophy (DOA) as well as DOA+, a phenotype characterized by more severe neurological deficits. OPA1 deficiency causes mitochondrial fragmentation and also disrupts cristae, respiration, mitochondrial DNA (mtDNA) maintenance, and cell viability. It has not yet been established whether phenotypic severity can be modulated by genetic modifiers of OPA1. We screened the entire known mitochondrial proteome (1,531 genes) to identify genes that control mitochondrial morphology using a first-in-kind imaging pipeline. We identified 145 known and novel candidate genes whose depletion promoted elongation or fragmentation of the mitochondrial network in control fibroblasts and 91 in DOA+ patient fibroblasts that prevented mitochondrial fragmentation, including phosphatidyl glycerophosphate synthase (PGS1). PGS1 depletion reduces CL content in mitochondria and rebalances mitochondrial dynamics in OPA1-deficient fibroblasts by inhibiting mitochondrial fission, which improves defective respiration, but does not rescue mtDNA depletion, cristae dysmorphology, or apoptotic sensitivity. Our data reveal that the multifaceted roles of OPA1 in mitochondria can be functionally uncoupled by modulating mitochondrial lipid metabolism, providing novel insights into the cellular relevance of mitochondrial fragmentation.

Keywords:  OPA1; genetic modifiers; high-throughput screening; mitochondrial dynamics; phospholipid metabolism

DOI:  https://doi.org/10.15252/emmm.202013579
J Cell Sci. 2020 Jan 01. pii: jcs.247379. [Epub ahead of print]

Mitochondrial survivin reduces oxidative phosphorylation in cancer cells by inhibiting mitophagy.

Amelia R Townley, Sally P Wheatley.

  Survivin is a cancer-associated protein that is pivotal for cellular life and death: it is an essential mitotic protein and an inhibitor of apoptosis. In cancer cells, a small pool of survivin localises to the mitochondria, the function of which remains to be elucidated. Here, we report that mitochondrial survivin inhibits the selective form of autophagy, called "mitophagy", causing an accumulation of respiratory defective mitochondria. Mechanistically the data reveal that survivin prevents recruitment of the E3-ubiquitin ligase Parkin to mitochondria and their subsequent recognition by the autophagosome. The data also demonstrate that cells in which mitophagy has been blocked by survivin expression have an increased dependency on glycolysis. As these effects were found exclusively in cancer cells they suggest that the primary act of mitochondrial survivin is to steer cells towards the implementation of the Warburg transition by inhibiting mitochondrial turnover, which enables them to adapt and survive.

Keywords:  Cancer; Mitochondria; Mitophagy; Respiration; Survivin

DOI:  https://doi.org/10.1242/jcs.247379
J Cell Sci. 2020 Jan 01. pii: jcs.244632. [Epub ahead of print]

Role of conserved regions of Tim22 in the structural organization of the carrier translocase.

Abhishek Kumar, Srujan Kumar Matta, Patrick D'Silva.

  Mitochondrial biogenesis requires efficient sorting of various proteins into different mitochondrial sub-compartments mediated by dedicated protein machinery present in the outer and inner membrane. Among them, the TIM22 complex enables the integration of complex membrane proteins with internal targeting signals into the inner membrane. Although the Tim22 forms the core of the complex, the dynamic recruitment of subunits to the channel is still enigmatic. The present study first-time highlights that IMS and TM4 regions of Tim22 are critically required for the interaction of the membrane-embedded subunits including, Tim54, Tim18, and Sdh3, thereby maintain the functional architecture of TIM22 translocase. On the other hand, TM1 and TM2 regions of Tim22 are important for the Tim18 association, while TM3 is exclusively required for the Sdh3 interaction. Moreover, the impairment in TIM22 complex assembly influences its translocase activity, mitochondrial network, and the viability of cells lacking mitochondrial DNA. Overall our findings provide compelling evidence to highlight the significance of conserved regions of Tim22 that are important for the maintenance of the TIM22 complex and mitochondrial integrity.

Keywords:  Mitochondria; Mitochondrial DNA; Mitochondrial morphology; Polytopic protein import; TIM22 complex

DOI:  https://doi.org/10.1242/jcs.244632
Front Neurosci. 2021 ;15 662242

Glycolytic Metabolism, Brain Resilience, and Alzheimer's Disease.

Xin Zhang, Nadine Alshakhshir, Liqin Zhao.

  Alzheimer's disease (AD) is the most common form of age-related dementia. Despite decades of research, the etiology and pathogenesis of AD are not well understood. Brain glucose hypometabolism has long been recognized as a prominent anomaly that occurs in the preclinical stage of AD. Recent studies suggest that glycolytic metabolism, the cytoplasmic pathway of the breakdown of glucose, may play a critical role in the development of AD. Glycolysis is essential for a variety of neural activities in the brain, including energy production, synaptic transmission, and redox homeostasis. Decreased glycolytic flux has been shown to correlate with the severity of amyloid and tau pathology in both preclinical and clinical AD patients. Moreover, increased glucose accumulation found in the brains of AD patients supports the hypothesis that glycolytic deficit may be a contributor to the development of this phenotype. Brain hyperglycemia also provides a plausible explanation for the well-documented link between AD and diabetes. Humans possess three primary variants of the apolipoprotein E (ApoE) gene - ApoE∗ϵ2, ApoE∗ϵ3, and ApoE∗ϵ4 - that confer differential susceptibility to AD. Recent findings indicate that neuronal glycolysis is significantly affected by human ApoE isoforms and glycolytic robustness may serve as a major mechanism that renders an ApoE2-bearing brain more resistant against the neurodegenerative risks for AD. In addition to AD, glycolytic dysfunction has been observed in other neurodegenerative diseases, including Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, strengthening the concept of glycolytic dysfunction as a common pathway leading to neurodegeneration. Taken together, these advances highlight a promising translational opportunity that involves targeting glycolysis to bolster brain metabolic resilience and by such to alter the course of brain aging or disease development to prevent or reduce the risks for not only AD but also other neurodegenerative diseases.

Keywords:  Alzheimer’s disease; apolipoprotein E; bioenergetics; biosynthesis; brain resilience; diabetes; glycolysis

DOI:  https://doi.org/10.3389/fnins.2021.662242
J Cell Sci. 2020 Jan 01. pii: jcs.242446. [Epub ahead of print]

A new brain mitochondrial sodium-sensitive potassium channel: effect of sodium ions on respiratory chain activity.

Javad Fahanik-Babaei, Bahareh Rezaee, Maryam Nazari, Nihad Torabi, Reza Saghiri, Remy Sauve, Afsaneh Eliassi.

  We have determined the electropharmacological properties of a new potassium channel from brain mitochondrial membrane by planar lipid bilayer method. Our results showed the presence of a channel with a conductance of 150 pS at potentials between 0 and -60 mV in 200 cis/50 trans mM KCl solutions. The channel was voltage-independent, with an open probability value ∼0.6 at different voltages. ATP did not affect current amplitude and Po at positive and negative voltages. Notably, adding iberiotoxin, charybdotoxin, lidocaine, and margatoxin had no effect on the channel behavior. Similarly, no changes were observed by decreasing the cis-pH to 6. Interestingly, the channel was inhibited by adding sodium in a dose dependent manner. Our results also indicated a significant increase in mitochondrial complex IV activity and membrane potential and decrease in complex I activity and mitochondrial ROS production in the presence of sodium ions. We propose that inhibition of mitochondrial K+ transport by Na ions on K+ channel opening may be important for cell protection and ATP synthesis.

Keywords:  Brain; Intracellular ion channel; Mitochondria; Mitochondrial respiratory chain; Potassium channels; Single channel

DOI:  https://doi.org/10.1242/jcs.242446
Fly (Austin). 2021 Dec;15(1): 60-72

In vivo assay and modelling of protein and mitochondrial turnover during aging.

Hans S Bell, John Tower.

  To maintain homoeostasis, cells must degrade damaged or misfolded proteins and synthesize functional replacements. Maintaining a balance between these processes, known as protein turnover, is necessary for stress response and cellular adaptation to a changing environment. Damaged mitochondria must also be removed and replaced. Changes in protein and mitochondrial turnover are associated with aging and neurodegenerative disease, making it important to understand how these processes occur and are regulated in cells. To achieve this, reliable assays of turnover must be developed. Several methods exist, including pulse-labelling with radioactive or stable isotopes and strategies making use of fluorescent proteins, each with their own advantages and limitations. Both cell culture and live animals have been used for these studies, in systems ranging from yeast to mammals. In vivo assays are especially useful for connecting turnover to aging and disease. With its short life cycle, suitability for fluorescent imaging, and availability of genetic tools, Drosophila melanogaster is particularly well suited for this kind of analysis.

Keywords:  Drosophila; aging; fluorescence microscopy; isotope labelling; mitophagy; protein turnover; video tracking

DOI:  https://doi.org/10.1080/19336934.2021.1911286
Dis Model Mech. 2020 Jan 01. pii: dmm.045229. [Epub ahead of print]

Mitochondrial damage and senescence phenotype of cells derived from a novel frataxin G127V point mutation mouse model of Friedreich's ataxia.

Daniel Fil, Balu K Chacko, Robbie Conley, Xiaosen Ouyang, Jianhua Zhang, Victor M Darley-Usmar, Aamir R Zuberi, Cathleen M Lutz, Marek Napierala, Jill S Napierala.

  Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin (FXN). Most FRDA patients are homozygous for large expansions of GAA repeat sequences in intron 1 of FXN, while a fraction of patients are compound heterozygotes with a missense or nonsense mutation in one FXN allele and expanded GAAs in the other. A prevalent missense mutation among FRDA patients changes a glycine at position 130 to valine (G130V). Herein, we report generation of the first mouse model harboring a Fxn point mutation. Changing the evolutionarily conserved glycine 127 in mouse Fxn to valine results in a failure to thrive phenotype in homozygous animals and a substantially reduced number of offspring. Like G130V in FRDA, the G127V mutation results in a dramatic decrease of Fxn protein without affecting transcript synthesis or splicing. FxnG127V mouse embryonic fibroblasts exhibit significantly reduced proliferation and increased cell senescence. These defects are evident in early passage cells and are exacerbated at later passages. Furthermore, increased frequency of mitochondrial DNA (mtDNA) lesions and fragmentation are accompanied by marked amplification of mtDNA in FxnG127V cells. Bioenergetics analyses demonstrate higher sensitivity and reduced cellular respiration of FxnG127V cells upon alteration of fatty acid availability. Importantly, substitution of FxnWT with FxnG127V is compatible with life and cellular proliferation defects can be rescued by mitigation of oxidative stress via hypoxia or induction of the NRF2 pathway. We propose FxnG127V cells as a simple and robust model for testing therapeutic approaches for FRDA.

Keywords:  Frataxin; Friedreich's ataxia; Mitochondria; Oxidative stress; Point mutation; Senescence

DOI:  https://doi.org/10.1242/dmm.045229
J Cell Sci. 2020 Jan 01. pii: jcs.237917. [Epub ahead of print]

Mitochondrial-nuclear heme trafficking is regulated by GTPases in control of mitochondrial dynamics and ER contact sites.

Osiris Martinez-Guzman, Mathilda M Willoughby, Arushi Saini, Jonathan V Dietz, Iryna Bohovych, Amy E Medlock, Oleh Khalimonchuk, Amit R Reddi.

  Heme is a cofactor and signaling molecule that is essential for much of aerobic life. All heme-dependent processes in eukaryotes require that heme is trafficked from its site of synthesis in the mitochondria to hemoproteins located throughout the cell. However, the mechanisms governing the mobilization of heme out of the mitochondria, and the spatio-temporal dynamics of these processes, are poorly understood. Herein, using genetically encoded fluorescent heme sensors, we developed a live cell assay to monitor heme distribution dynamics between the mitochondrial inner-membrane, where heme is synthesized, and the mitochondrial matrix, cytosol, and nucleus. Surprisingly, heme trafficking to the nucleus is ∼25% faster than to the cytosol or mitochondrial matrix, which are nearly identical, potentially supporting a role for heme as a mitochondrial-nuclear retrograde signal. Moreover, we discovered that the heme synthetic enzyme, 5-aminolevulinic acid synthase (ALAS), and GTPases in control of the mitochondrial dynamics machinery, Mgm1 and Dnm1, and ER contact sites, Gem1, regulate the flow of heme between the mitochondria and nucleus. Overall, our results indicate that there are parallel pathways for the distribution of bioavailable heme.

Keywords:  Heme; Heme transport; Mitochondrial dynamics; Yeast

DOI:  https://doi.org/10.1242/jcs.237917
J Cell Sci. 2020 Jan 01. pii: jcs.240374. [Epub ahead of print]

Cardiolipin is required for membrane docking of mitochondrial ribosomes and protein synthesis.

Richard G Lee, Junjie Gao, Stefan J Siira, Anne-Marie Shearwood, Judith A Ermer, Vinzenz Hofferek, James C Mathews, Minghao Zheng, Gavin E Reid, Oliver Rackham, Aleksandra Filipovska.

  The mitochondrial inner membrane contains a unique phospholipid known as cardiolipin (CL), which stabilises the protein complexes embedded in the membrane and supports its overall structure. Recent evidence indicates that the mitochondrial ribosome may associate with the inner membrane to facilitate co-translational insertion of the hydrophobic oxidative phosphorylation (OXPHOS) proteins into the inner membrane. We generated three mutant knockout cell lines for the cardiolipin biosynthesis gene Crls1 to investigate the effects of cardiolipin loss on mitochondrial protein synthesis. Reduced CL levels caused altered mitochondrial morphology and transcriptome-wide changes that were accompanied by reduced uncoordinated mitochondrial translation rates and impaired respiratory supercomplex formation. Aberrant protein synthesis was caused by impaired formation and distribution of mitochondrial ribosomes. Reduction or loss of cardiolipin resulted in divergent mitochondrial and endoplasmic reticulum stress responses. We show that cardiolipin is required to stabilise the interaction of the mitochondrial ribosome with the membrane via its association with OXA1 during active translation. This interaction facilitates insertion of newly synthesised mitochondrial proteins into the inner membrane and stabilises the respiratory supercomplexes.

Keywords:  Mitochondrial membranes; Mitochondrial ribosomes; Protein synthesis

DOI:  https://doi.org/10.1242/jcs.240374
ACS Chem Neurosci. 2021 May 20.

The Protective Effects of Dexmedetomidine against Hypoxia/Reoxygenation-Induced Inflammatory Injury and Permeability in Brain Endothelial Cells Mediated by Sigma-1 Receptor.

Qin Zhao, Shoushui Yu, Yong Ling, Shiyuan Hao, Jia Liu.

  Cerebral ischemia-reperfusion injury (CIRI) mainly arises from the clinical treatment of ischemic stroke, induced by the blood-brain barrier (BBB) disruption and infiltrated inflammation. The Sigma-1 receptor (Sigma-1R) is a novel target for neuroprotection, and the α2-receptor agonist pain medication dexmedetomidine displays a neuroprotective effect through activating Sigma-1R. The present study aims to investigate the potential therapeutic effect of dexmedetomidine in a mouse stroke model and hypoxia/reoxygenation(OGD/R)-induced brain endothelial dysfunction. First, we found that Sigma-1R was significantly upregulated in middle cerebral artery occlusion (MCAO) mice by the administration of dexmedetomidine. In vivo experiments revealed that dexmedetomidine ameliorated hyperpermeability of the blood-brain barrier (BBB), lowered the expression level of Occludin, and impaired brain function as measured by neurological scores in MCAO mice. In vitro assays show that dexmedetomidine alleviated OGD/R-caused cytotoxicity, hyperpermeability, abnormal expression of Occludin, and inflammatory factors in human brain microvascular endothelial cells (HBMVECs). Moreover, blockage of Sigma-1R by its antagonist BD1047 abolished the neuroprotective property of dexmedetomidine in both animal and cell culture experiments. On the basis of these findings, we conclude that dexmedetomidine therapy shows neuroprotection in MCAO mice. Mechanistically, dexmedetomidine alleviated hypoxia/reoxygenation-induced cerebral endothelial dysfunction by activating the Sigma-1R-mediated signaling pathway.

Keywords:  BBB; MCAO; Occludin; Sigma-1 receptor (Sigma-1R); Stroke; hypoxia/reoxygenation(OGD/R)

DOI:  https://doi.org/10.1021/acschemneuro.1c00032
Curr Neuropharmacol. 2021 May 16.

Mitochondrial dysfunction in Alzheimer's disease: Opportunities for drug development.

Shiveena Bhatia, Rishi Rawal, Pratibha Sharma, Tanveer Singh, Manjinder Singh, Varinder Singh.

  Alzheimer's disease (AD) is one of the major reasons for 60-80% of cases of senile dementia occurring as a result of the accumulation of plaques and tangles in the hippocampal and cortical neurons of the brain leading to neurodegeneration and cell death. The other pathological features of AD comprise of abnormal microvasculature, network abnormalities, interneuronal dysfunction, increased β-amyloid production, and reduced clearance, increased inflammatory response, elevated production of reactive oxygen species, impaired brain metabolism, hyperphosphorylation of tau, and disruption of acetylcholine signaling. Among all these pathologies, mitochondrial dysfunction (MD), regardless of being an inciting insult or a consequence of the alterations, is related to all the associated AD pathologies. Observed altered mitochondrial morphology, distribution, and movement increased oxidative stress, dysregulation of enzymes involved in mitochondrial functioning, impaired brain metabolism, and impaired mitochondrial biogenesis in AD subjects suggest the involvement of mitochondrial malfunction in the progression of AD. Various pre-clinical and clinical evidence establishing MD as a key mediator in the progression of neurodegeneration in AD are reviewed and discussed with an aim to foster future MD-based drug development research for the management of AD.

Keywords:  Alzheimer's disease; Apoptosis; β-amyloid plaques; Mitochondrial dysfunction; Oxidative stress; Tau proteins

DOI:  https://doi.org/10.2174/1570159X19666210517114016
Sci Rep. 2021 May 19. 11(1): 10597

Intranasal delivery of mitochondria for treatment of Parkinson's Disease model rats lesioned with 6-hydroxydopamine.

Jui-Chih Chang, Yi-Chun Chao, Huei-Shin Chang, Yu-Ling Wu, Hui-Ju Chang, Yong-Shiou Lin, Wen-Ling Cheng, Ta-Tsung Lin, Chin-San Liu.

The feasibility of delivering mitochondria intranasally so as to bypass the blood-brain barrier in treating Parkinson's disease (PD), was evaluated in unilaterally 6-OHDA-lesioned rats. Intranasal infusion of allogeneic mitochondria conjugated with Pep-1 (P-Mito) or unconjugated (Mito) was performed once a week on the ipsilateral sides of lesioned brains for three months. A significant improvement of rotational and locomotor behaviors in PD rats was observed in both mitochondrial groups, compared to sham or Pep-1-only groups. Dopaminergic (DA) neuron survival and recovery > 60% occurred in lesions of the substantia nigra (SN) and striatum in Mito and P-Mito rats. The treatment effect was stronger in the P-Mito group than the Mito group, but the difference was insignificant. This recovery was associated with restoration of mitochondrial function and attenuation of oxidative damage in lesioned SN. Notably, P-Mito suppressed plasma levels of inflammatory cytokines. Mitochondria penetrated the accessory olfactory bulb and doublecortin-positive neurons of the rostral migratory stream (RMS) on the ipsilateral sides of lesions and were expressed in striatal, but not SN DA neurons, of both cerebral hemispheres, evidently via commissural fibers. This study shows promise for intranasal delivery of mitochondria, confirming mitochondrial internalization and migration via RMS neurons in the olfactory bulb for PD therapy.

DOI: https://doi.org/10.1038/s41598-021-90094-w
Trends Pharmacol Sci. 2021 May 12. pii: S0165-6147(21)00072-9. [Epub ahead of print]

Targeting the mitochondrial chaperone TRAP1: strategies and therapeutic perspectives.

Stefano A Serapian, Carlos Sanchez-Martín, Elisabetta Moroni, Andrea Rasola, Giorgio Colombo.

  TRAP1, the mitochondrial isoform of heat shock protein (Hsp)90 chaperones, is a key regulator of metabolism and organelle homeostasis in diverse pathological states. While selective TRAP1 targeting is an attractive goal, classical active-site-directed strategies have proved difficult, due to high active site conservation among Hsp90 paralogs. Here, we discuss advances in developing TRAP1-directed strategies, from lead modification with mitochondria delivery groups to the computational discovery of allosteric sites and ligands. Specifically, we address the unique opportunities that targeting TRAP1 opens up in tackling fundamental questions on its biology and in unveiling new therapeutic approaches. Finally, we show how crucial to this endeavor is our ability to predict the activities of TRAP1-selective allosteric ligands and to optimize target engagement to avoid side effects.

Keywords:  drug design; mitochondrial proteostasis; molecular chaperones; molecular dynamics

DOI:  https://doi.org/10.1016/j.tips.2021.04.003
Metab Brain Dis. 2021 May 21.

The effect of Crocin on TFAM and PGC-1α expression and Catalase and Superoxide dismutase activities following cholestasis-induced neuroinflammation in the striatum of male Wistar rats.

Mohammad-Reza Eteghadi, Mohammad Nasehi, Salar Vaseghi, Saeed Hesami-Tackallou.

  Bile secretion is a physiological function that is disrupted following Bile Duct Ligation (BDL) and induces cholestasis. Cholestasis is a bile flow reduction that induces apoptosis, oxidative stress, and inflammation, and alters the expression of genes. Evidence shows the relationship between cholestasis and neuroinflammation. Cholestasis via attenuating mitochondrial biogenesis and anti-oxidant activity can induce neuroinflammation and apoptosis. Mitochondrial transcriptional factor A (TFAM) and Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) are involved in mitochondrial biogenesis, and TFAM, PGC-1α, Catalase (CAT), and Superoxide dismutase (SOD) have a role in upregulating antioxidant pathways. On the other hand, many studies have shown the neuroprotective effects of Crocin, the water-soluble carotenoid of Saffron (Crocus sativus L.). In this study, we aimed to investigate the effect of Crocin on the level of TFAM, PGC-1α, CAT, and SOD following cholestasis-induced neuroinflammation in the rat's striatum. Cholestasis was induced by BDL surgery and administration of Crocin was intraperitoneal, at the dose of 30 mg/kg every day, 24 h after BDL surgery up to thirty days. The results showed that TFAM, PGC-1α, and SOD were decreased following cholestasis; while, CAT was increased. In addition, Crocin restored the effects of cholestasis on the level of TFAM, PGC-1α, and SOD. In conclusion, Crocin may have improvement effects on cholestasis-induced neuroinflammation in the rat's striatum.

Keywords:  Catalase (CAT); Crocin; Mitochondrial transcriptional factor A (TFAM); Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α); Striatum; Superoxide dismutase (SOD)

DOI:  https://doi.org/10.1007/s11011-021-00748-x
EMBO J. 2021 May 21. e105990

NPC1 regulates the distribution of phosphatidylinositol 4-kinases at Golgi and lysosomal membranes.

Candice Kutchukian, Oscar Vivas, Maria Casas, Julia G Jones, Scott A Tiscione, Sergi Simó, Daniel S Ory, Rose E Dixon, Eamonn J Dickson.

  Cholesterol and phosphoinositides (PI) are two critically important lipids that are found in cellular membranes and dysregulated in many disorders. Therefore, uncovering molecular pathways connecting these essential lipids may offer new therapeutic insights. We report that loss of function of lysosomal Niemann-Pick Type C1 (NPC1) cholesterol transporter, which leads to neurodegenerative NPC disease, initiates a signaling cascade that alters the cholesterol/phosphatidylinositol 4-phosphate (PtdIns4P) countertransport cycle between Golgi-endoplasmic reticulum (ER), as well as lysosome-ER membrane contact sites (MCS). Central to these disruptions is increased recruitment of phosphatidylinositol 4-kinases-PI4KIIα and PI4KIIIβ-which boosts PtdIns4P metabolism at Golgi and lysosomal membranes. Aberrantly increased PtdIns4P levels elevate constitutive anterograde secretion from the Golgi complex, and mTORC1 recruitment to lysosomes. NPC1 disease mutations phenocopy the transporter loss of function and can be rescued by inhibition or knockdown of either key phosphoinositide enzymes or their recruiting partners. In summary, we show that the lysosomal NPC1 cholesterol transporter tunes the molecular content of Golgi and lysosome MCS to regulate intracellular trafficking and growth signaling in health and disease.

Keywords:  Niemann-Pick Type C; mTORC; membrane contact sites; neurodegeneration; phosphoinositides

DOI:  https://doi.org/10.15252/embj.2020105990
J Cell Sci. 2020 Jan 01. pii: jcs.245589. [Epub ahead of print]

Perinuclear mitochondrial clustering, increased ROS levels, and HIF1 are required for the activation of HSF1 by heat stress.

Saloni Agarwal, Subramaniam Ganesh.

  Heat shock response (HSR) is a conserved cellular defensive response against stresses such as temperature, oxidative stress, and heavy metals. A significant group of players in HSR is the set of molecular chaperones, known as heat shock proteins (HSPs) that assist in the refolding of unfolded proteins and prevent the accumulation of damaged proteins. HSP genes are activated by the HSF1 transcription factor-a master regulator of the HSR pathway. A variety of stressors activates HSF1, but the key molecular players and the process that directly contribute to the HSF1 activation remains unclear. In this study, we show that heat shock induces perinuclear clustering of mitochondria in mammalian cells, and this clustering is essential for the activation of HSR. We also show that this perinuclear clustering of mitochondria results in the increased levels of ROS in the nucleus, leading to the activation of hypoxia-inducible factor-1α (HIF-1α). Finally, we provide evidence to suggest that HIF-1α is one of the critical regulators of HSF1 and that HIF-1α is essential for the activation of HSR during a heat shock.

Keywords:  Chaperones; Hypoxia response; Mitochondrial transport; Oxidative stress; Stress response; Transcriptional regulation

DOI:  https://doi.org/10.1242/jcs.245589